The longitudinal loss of islet autoantibody responses from diagnosis of type 1 diabetes occurs progressively over follow-up and is determined by low autoantibody titres, early-onset, and genetic variants.

The clinical usefulness of post-diagnosis islet autoantibody levels is unclear and factors that drive autoantibody persistence are poorly defined in type 1 diabetes (T1D). Our aim was to characterise the longitudinal loss of islet autoantibody responses after diagnosis in a large, prospectively sampled UK cohort. Participants with T1D [n = 577] providing a diagnosis sample [range -1.0 to 2.0 years] and at least one post-diagnosis sample (<32.0 years) were tested for autoantibodies to glutamate decarboxylase 65 (GADA), islet antigen-2 (IA-2A), and zinc transporter 8 (ZnT8A). Select HLA and non-HLA SNPs were considered. Non-genetic and genetic factors were assessed by multivariable logistic regression models for autoantibody positivity at initial sampling and autoantibody loss at final sampling. For GADA, IA-2A, and ZnT8A, 70.8%, 76.8%, and 40.1%, respectively, remained positive at the final sampling. Non-genetic predictors of autoantibody loss were low baseline autoantibody titres (P < 0.0001), longer diabetes duration (P < 0.0001), and age-at-onset under 8 years (P < 0.01--0.05). Adjusting for non-genetic covariates, GADA loss was associated with low-risk HLA class II genotypes (P = 0.005), and SNPs associated with autoimmunity RELA/11q13 (P = 0.017), LPP/3q28 (P = 0.004), and negatively with IFIH1/2q24 (P = 0.018). IA-2A loss was not associated with genetic factors independent of other covariates, while ZnT8A loss was associated with the presence of HLA A*24 (P = 0.019) and weakly negatively with RELA/11q13 (P = 0.049). The largest longitudinal study of islet autoantibody responses from diagnosis of T1D shows that autoantibody loss is heterogeneous and influenced by low titres at onset, longer duration, earlier age-at-onset, and genetic variants. These data may inform clinical trials where post-diagnosis participants are recruited.

Islet autoantibody profiles associated with higher diabetes risk in Lithuanian compared with English schoolchildren.

During a 15-year period, the incidence of type 1 diabetes has doubled in Lithuania, while increasing by a third in England; however, England still has a higher incidence. Analysis of sera collected from non-diabetic schoolchildren from Lithuania and England more than 20 years ago showed a similar number of multiple autoantibody-positive schoolchildren between the populations, but a higher prevalence of islet antigen-2 autoantibodies (IA-2A) in English schoolchildren. We aimed to use recently developed, more specific islet autoantibody tests to characterize differences in humoral autoimmunity between these two general population cohorts in greater detail. Samples from 88 Lithuanian and 133 English schoolchildren previously found islet autoantibody-positive were selected for measurement of additional islet autoantibodies by radioimmunoassay. Samples were tested for autoantibodies to zinc transporter 8 (ZnT8A), GAD (96-585), the protein tyrosine phosphatase region of islet antigen-2 (PTPA) and the related IA-2ßA, while autoantibodies to IA-2A were reassayed using the current harmonized method. IA-2-related autoantibodies PTPA (0·13 versus 0·45%, P = 0·027) and IA-2ßA (0 versus 0·35%, P < 0·001), but not IA-2A measured using the harmonized method, were less common in Lithuanian compared to English schoolchildren. Lithuanian schoolchildren who were islet autoantibody-positive were positive for fewer biochemical autoantibodies compared with English schoolchildren (P = 0·043). Background rates of islet autoimmunity in childhood differ subtly between countries, which have different incidences of type 1 diabetes. The optimal screening strategy (age and combination of markers) for detection of islet autoimmunity may vary between countries, dependent upon the pattern of autoantibodies found in the general population.

The first 142 amino acids of glutamate decarboxylase do not contribute to epitopes recognized by autoantibodies associated with Type 1 diabetes.

AIMS: Glutamate decarboxylase (GAD) antibodies are the most widely used predictive marker for Type 1 diabetes, but many individuals currently found to be GAD antibody-positive are unlikely to develop diabetes. We have shown previously that radioimmunoassays using N-terminally truncated 35 S-GAD65 (96-585) offer better disease specificity with similar sensitivity to full-length 35 S-GAD65 (1-585). To determine whether assay performance could be improved further, we evaluated a more radically truncated 35 S-GAD65 (143-585) radiolabel. METHODS: Samples from people with recent-onset Type 1 diabetes (n = 157) and their first-degree relatives (n = 745) from the Bart's-Oxford family study of childhood diabetes were measured for GAD antibodies using 35 S-labelled GAD65 (143-585). These were screened previously using a local radioimmunoassay with 35 S-GAD65 (1-585). A subset was also tested by enzyme-linked immunosorbent assay (ELISA), which performs well in international workshops, but requires 10 times more serum. Results were compared with GAD antibody measurements using 35 S-GAD65 (1-585) and 35 S-GAD65 (96-585). RESULTS: Sensitivity of GAD antibody measurement was maintained using 35 S-GAD65 (143-585) compared with 35 S-GAD65 (1-585) and 35 S-GAD65 (96-585). Specificity for Type 1 diabetes was improved compared with 35 S-GAD65 (1-585), but was similar to 35 S-GAD65 (96-585). Relatives found to be GAD antibody-positive using these truncated labels were at increased risk of diabetes progression within 15 years, compared with those positive for GAD(1-585) antibody only, and at similar risk to those found GAD antibody-positive by ELISA. CONCLUSIONS: The first 142 amino acids of GAD65 do not contribute to epitopes recognized by Type 1 diabetes-associated GAD antibodies. Low-volume radioimmunoassays using N-terminally truncated 35 S-GAD65 are more specific than those using full-length GAD65 and offer practical alternatives to the GAD antibody ELISA for identifying children at increased risk of Type 1 diabetes.

A quarter of patients with type 1 diabetes have co-existing non-islet autoimmunity: the findings of a UK population-based family study.

Individuals with type 1 diabetes (T1D) are at increased risk of coeliac disease (CD), autoimmune thyroiditis and autoimmune gastritis, but the absolute risks are unclear. The aim of this study was to investigate the prevalence of autoantibodies to tissue transglutaminase (TGA), thyroid peroxidase (TPOA) and gastric H+ /K+ -ATPase (ATPA) and their genetic associations in a well-characterized population-based cohort of individuals with T1D from the Bart's-Oxford family study for whom islet autoantibody prevalence data were already available. Autoantibodies in sera from 1072 patients (males/females 604/468; median age 11·8 years, median T1D duration 2·7 months) were measured by radioimmunoassays; HLA class II risk genotype was analysed in 973 (91%) using polymerase chain reaction with sequence specific primers (PCR-SSP). The prevalence of TGA (and/or history of CD), TPOA and ATPA in patients was 9·0, 9·6 and 8·2%, respectively; 3·1% had two or more autoantibodies. Females were at higher risk of multiple autoimmunity; TGA/CD were associated with younger age and TPOA with older age. ATPA were uncommon in patients under 5 years, and more common in older patients. Anti-glutamate decarboxylase autoantibodies were predictive of co-existing TPOA/ATPA. TGA/CD were associated with human leucocyte antigen (HLA) DR3-DQ2, with the DR3-DQ2/DR3-DQ2 genotype conferring the highest risk, followed by DR4-DQ8/DR4-DQ8. ATPA were associated with DR3-DQ2, DRB1*0404 (in males) and the DR3-DQ2/DR4-DQ8 genotype. TPOA were associated with the DR3-DQ2/DR3-DQ2 genotype. Almost one-quarter of patients diagnosed with T1D aged under 21 years have at least one other organ-specific autoantibody. HLA class II genetic profiling may be useful in identifying those at risk of multiple autoimmunity.

An increased frequency of NK cell receptor and HLA-C group 1 combinations in early-onset type 1 diabetes.

AIMS/HYPOTHESIS: Natural killer (NK) cells serve as primary immune surveillance and are partially regulated by combinations of killer immunoglobulin-like receptor (KIR) genes and their HLA class I ligands. Alterations in NK cell activity have been associated with type 1 diabetes. The aim of this study was to determine whether KIR-HLA class I gene frequency: (1) is altered in a current population with type 1 diabetes compared with healthy controls; and (2) has changed over the half century in which the incidence of type 1 diabetes has increased rapidly. METHODS: KIR-HLA class I gene frequencies were compared in 551 individuals diagnosed with type 1 diabetes ≤ 15 years of age (394 in a current cohort and 157 from the historical 'Golden Years' cohort) and 168 healthy controls. The overall balance of activation and inhibition was analysed using KIR-HLA genotype models. RESULTS: Children with type 1 diabetes who were positive for KIR2DS2/KIR2DL2 and KIR2DL3 were more often homozygous for HLA-C group 1 and this effect was strongest in children diagnosed with diabetes before the age of 5 years (p = 0.003, corrected p [p (corr)] = 0.012) and (p = 0.001, p (corr) = 0.004), respectively. Children with type 1 diabetes have fewer inhibitory KIRs with their corresponding ligands compared with healthy controls (p = 1.9 × 10(-4)). This pattern of NK activation has not changed significantly in individuals with type 1 diabetes over the last half century. CONCLUSIONS/INTERPRETATION: Activating combinations of KIR-HLA genes are more frequent in young children with type 1 diabetes diagnosed in the first 5 years of life, suggesting that NK cell responses may be altered in this group.

Diabetes mellitus among young adults in Sri Lanka--role of GAD antibodies in classification and treatment: the Sri Lanka Young Diabetes study.

AIMS/HYPOTHESIS: Diabetes mellitus is increasing among young adult South Asians. The aim of this study was to determine the prevalence and phenotypic characteristics of diabetes subtypes based on GAD65 autoantibody (GADA) status in those with young adult-onset diabetes in Sri Lanka. METHODS: Clinical, metabolic and GADA data were available for 992 consecutively recruited individuals with diabetes aged < or =45 years (age at diagnosis 16-40 years). Participants were classified according to the following definitions: type 1 diabetes, insulin-dependent <6 months from diagnosis; latent autoimmune diabetes in adults (LADA), GADA-positive, age > or =30 years and insulin-independent > or =6 months from diagnosis; type 2 diabetes, GADA-negative and insulin-independent > or =6 months from diagnosis. RESULTS: The median (interquartile range) age at diagnosis and diabetes duration were 33.0 (29.0-36.1) and 4.0 (1.1-7.1) years, respectively; 42.1% were male. GADA positivity was seen in 5.4% of participants (n = 54) and GADA levels negatively correlated with age at diagnosis (p < 0.0001), BMI (p < 0.0001) and time to insulin requirement (p = 0.006). Type 1 diabetes, type 2 diabetes and LADA were present in 7.0%, 89.7% and 2.6%, respectively. The remaining 0.7% of the participants were GADA-positive, insulin independent > or =6 months from diagnosis and were diagnosed at age <30 years. The metabolic syndrome and homeostasis model assessment of beta cell function (HOMA %B) were lowest in GADA-positive type 1 diabetes and increased progressively in latent autoimmune diabetes, GADA-negative type 1 diabetes and type 2 diabetes. Among those requiring insulin, 69.2% had fasting C-peptide levels in the lowest quartile, whereas only 19.5% were GADA-positive (p < 0.0001). CONCLUSIONS/INTERPRETATION: The prevalence of GADA-positive autoimmune diabetes is low among individuals with young adult-onset diabetes in Sri Lanka. Young-onset diabetic phenotypes appear as a continuum from autoimmune type 1 diabetes to type 2 diabetes.

Esophageal carcinosarcoma.

Carcinosarcoma is an uncommon malignancy of the esophagus that presents as a bulky intraluminal polypoid lesion of the esophagus. Histologically, both carcinomatous and sarcomatous components are seen. Because of accelerated intraluminal growth, esophageal carcinosarcoma often presents relatively early. This report describes a 64-year-old man with carcinosarcoma who was successfully treated with an esophagectomy. As in typical squamous cell carcinoma, early detection and treatment by surgical resection are needed to produce significant long-term survival.

Weight-height relationships among eight populations of West African origin: the case against constant BMI standards.

OBJECTIVE: To ascertain whether constant body mass index (BMI) standards are appropriate in genetically similar populations. DESIGN: Data are taken from the International Collaborative Study of Hypertension in Blacks (ICSHIB), an observational study. SUBJECTS: Individuals of African descent who were included in ICSHIB. Subjects lived in eight different sites: Barbados; Cameroon (urban and rural); Jamaica; Manchester, UK; Maywood, IL; urban Nigeria; and St Lucia. MEASUREMENTS: Weight and height. RESULTS: Constant BMI standards effectively argue for the constancy of slope of the linear regression equations of In(weight) on In(height) across populations. Linear regression results indicate that the height/weight relationship implied by the use of constant BMI standards, is not found in these populations and that there is much variation across groups. CONCLUSION: The use of constant BMI standards in classifying individuals prognostically may be unwise, even in genetically similar populations.

The relation between income and mortality in U.S. blacks and whites.

Differential mortality exists in the United States both between racial/ethnic groups and along gradients of socioeconomic status. The specification of statistical models for processes underlying these observed disparities has been hindered by the fact that social and economic quantities are distributed in a highly nonrandom manner throughout the population. We sought to provide a substantive foundation for model development by representing the shape of the income-mortality relation by racial/ethnic group. We used data on black and white men and women from the longitudinal component of the National Health Interview Survey (NHIS), 1986-1990, which provided 1,191,824 person-years of follow-up and 12,165 mortal events. To account for family size when considering income, we used the ratio of annual family income to the federal poverty line for a family of similar composition. To avoid unnecessary categorizations and prior assumptions about model form, we employed kernel smoothing techniques and calculated the continuous mortality surface across dimensions of adjusted income and age for each of the gender and racial/ethnic groups. Representing regions of equal mortality density with contour plots, we observed interactions that need to be accommodated by any subsequent statistical models. We propose two general theories that provide a foundation for more elaborate and testable hypotheses in the future.

Leptin and body composition of Nigerians, Jamaicans, and US blacks.

The role of leptin in humans remains controversial. Leptin concentrations are highly correlated with body fat stores. We tested whether or not this relation was consistent across the range of body composition encompassing the lean as well as the obese. Individuals participating in community-based comparative research in Nigeria (n = 363), Jamaica (n = 372), and the United States (Maywood, IL; n = 699) had their plasma leptin concentrations and body compositions (with bioelectrical impedance analysis) measured. All participants identified themselves as being black. Body mass index (in kg/m2) ranged from 14 to 62. Large differences in mean plasma leptin were noted across populations for both men and women in Nigeria, Jamaica, and the United States, respectively (men: 2.8, 3.9, and 6.8 microg/L; women: 10.3, 18.6, and 27.7 microg/L). An exponential function fit the relation between percentage body fat or total fat mass and leptin for men and women at each site. For women and men the exponential function with either percentage body fat or total fat mass was of the same shape, but increased by a constant in women, yielding higher leptin concentrations than in men at every level of body fat. On the basis of this broad distribution of body composition, the data suggest an exponential response of leptin to increases in body fat stores, consistent with the development of leptin resistance in individuals developing obesity. These findings likewise confirm that men and women exhibit different set points in terms of leptin production.

Relationship between blood pressure and body mass index in lean populations.

Associations between body mass index (BMI) and blood pressure (BP) have been consistently observed, but remain poorly understood. One unresolved question is whether there is a linear relationship across the entire BMI range. We investigated this question among 11,235 adult men and women from seven low-BMI populations in Africa and the Caribbean. We used kernel smoothing and multivariate linear and spline regression modeling to examine gender differences in the relationship and to test for a threshold. Age-adjusted slopes of BP on BMI were uniformly higher in men than women, with pooled slope ratios of 2.00 and 2.20 for systolic and diastolic BPs, respectively. Men displayed no evidence of age modification or nonlinearity in the relationship, and the age-adjusted slope of systolic BP on BMI was 0.90 (95% confidence interval [CI], 0.76 to 1.04). Women demonstrated both age modification and nonlinearity. For both younger (<45 years) and older (45+ years) women, the optimal change point for a single threshold model was found to be 21 kg/m2. Slopes of systolic BP on BMI above this threshold were positive and significant: 0.68 (95% CI, 0.54 to 0.81) and 0.53 (95% CI, 0.29 to 0.76) for younger and older women, respectively. Slopes below the threshold were essentially zero for both groups of women, and the difference between the slopes above and below the threshold was significant for younger women (P=.019). In summary, we observed a threshold at 21 kg/m2 in the relationship between BMI and BP for women but not for men. This contributes to the effort to identify the mechanisms that underlie this relationship and how they differ by gender.

Mortality from coronary heart disease and cardiovascular disease among adult U.S. Hispanics: findings from the National Health Interview Survey (1986 to 1994).

OBJECTIVES: We sought to estimate the coronary heart disease (CHD) and cardiovascular disease (CVD) mortality experience of U.S. Hispanics. BACKGROUND: Limited information is available concerning the mortality from CHD among U.S. Hispanics, the nation's second largest minority group. METHODS: The study used data from the National Health Interview Survey (1986 to 1994), including representative national samples of 246,239 non-Hispanic whites, 38,042 blacks and 14,965 Hispanics who were > or = 45 years old at baseline. Mean follow-up of mortality was 5 years (range 1 to 10). RESULTS: During the follow-up period, 27,702 whites (11%), 4,976 blacks (13%) and 1,061 Hispanics (7%) died. Among men, the age-adjusted total mortality per 100,000 person-years was 3,089 in whites and 2,466 in Hispanics, and among women, it was 1,897 and 1,581 in whites and Hispanics, respectively. The Hispanic/white mortality rate ratio for CHD was 0.77 (95% confidence interval [CI] 0.64 to 0.93) and 0.82 (95% CI 0.66 to 1.01) for men and women, respectively. The rate ratio was 0.79 (95% CI 0.68 to 0.91) and 0.80 (95% CI 0.69 to 0.94), respectively, for mortality from cardiovascular diseases. Given the lower all-cause mortality in Hispanics, the proportion of total deaths due to CHD and CVD was similar between the two populations for the same gender and were, respectively, 29.7% and 44.7% in white men, 28.1% and 44.3% in Hispanic men, 24.9% and 43.2% in white women and 24.1% and 41% in Hispanic women. CONCLUSIONS: These data from a cohort of a large national sample are consistent with vital statistics that show that all-cause, CHD and CVD mortality is approximately 20% lower among adult Hispanics than among whites in the United States.

Radiographic decision-making by the emergency physician.

To assist emergency clinicians in appropriately requesting x-ray examinations of their patients, this article looks at the factors that affect the decision to order a radiograph, describes methods of determining the efficacy of a radiograph, discusses several radiographic studies frequently requested by emergency physicians and when they are most efficacious, and reviews the ways physician decision-making may be influenced to decrease radiographic wastage.